Design and Fabrication of an Electrochemical Microreactor and its Use in Electroorganic Synthesis Kevin George Watts PhD Thesis 2013 Table of Contents Abstract …………………………………...………………………………………………v Abbreviations…..………………………………..…………………………………..vi-viii Acknowledgements………………………………………………………………………ix 1. General introduction 1. Electroorganic chemistry……………………………...…………………2 1.1 History of electrochemi stry………………………………..……......2 1.2 Industrial electrochemistry……………………..……………………4 1.3 Fundamentals……………………………………...………………....6 1.4 Electrode reactions…………………..……………………………....7 1.5 Physical phenomena ………………………………..…………….....9 1.5.1 The electrochemical double layer…………………………..9 1.5.2 Mass transport…..………………..………………………..11 1.5.2.1 Diffusion……….…………………………………12 1.5.2.2 Migration…………..…………..…………………12 1.5.2.3 Convection…..….……..………………………….12 1.6 Methods of electrolysis…………………………………...………...13 1.6.1 Controlled potential electrolysis……………………...……..13 1.6.2 Controlled current electrolysis……………………..……….14 1.7 Cell design .…...………………………..……………………………17 1.7.1 Batch cell s…………………………..………………………17 1.7.1.1 Undivided cell s…………………………..……………...17 1.7.1.2 Divided cell s………………………………..…………...18 1.7.2 Flow through cell s………………………….….……………19 1.7.3 Electrode materials……………………….….……………...19 1.7.4 Reference electrodes……………………….……………….21 1.7.5 Diaphragms…………………...……………………………..22 1.8 Solvent eff ects…………………………..…………………………..22 1.8.1 Protic so lvents……………..………………………………..23 1.8.2 Aprotic so lvents…………………………………..…………24 1.9 Supporting electrolytes…………………………..………………….24 i 1.9.1 Anionic………………………..…………………………….25 1.9.2 Cati on ic………………...……………………………………25 1.10 Electrochemical intermediates and reactions………..……...26 1.10.1 Direct intermediate formation…………….…….…………..27 1.10.1.1 Carbon-carbon bond formation…………..…………27 1.10.1.1.1 Polar/Umpolung reactions………………..……..27 1.10.1.1.2 Radical carbon-carbon bond formation….……..29 1.10.1.2 Functional group interconversion…………..……….30 1.10.2 Indirect electrochemistry……………..……………………..32 2. Microreactors for organic synthesis………………………...………..…34 2.1 Introduction to flow chemistry……………………….……………..34 2.2 Microreactor set-up…………………………....…………………....34 2.3 Chip/reactor design……………………….………….……………. 36 2.4 Advantages of flow chemistry……………………………..………..37 2.4.1 Efficient mi xing…………………………………..…………38 2.4.2 Heat management……………………..…………………….41 2.4.3 Specific control of residence times……………..…………..43 2.4.4 Handling dangerous compounds…………….……………..44 2.4.5 Multi-step syntheses………………….…………………….45 2.4.6 Online analysis and self optimising tec hn iqu es……….…...46 2.4.7 Scaling up reactions…………..…………………………….48 2.5 Pumping techniques………………...……………………………….49 2.6 Interfacial reactions…………………..……………………………..50 3. Electrochemical microreactors…………………………….……….…...51 3.1 Advantages of electrochemical microreactors…………...………….51 3.2 Designs of electrochemical microreactors………………..………...53 3.2.1 Plate to plate electrodes……………………..………………53 3.2.2 Divided cell microreactors…………………..……………...60 3.2.3 Interdigitated band electrodes………………..……………..64 4. References…………………………..…………………………………..66 2. Design and fabrication of an electrochemical microreactor 2.1 Construction and testing of a prototype……………………...………….73 2.2 Conclusions………………………………..……………………………83 2.3 Experimental……………………..……………………………………...85 ii 2.4 References………………………..……………………………………..86 3. Electrochemical synthesis of diaryliodonium salts in flow 3.1 Introduction………………………………………..……………………91 3.1.1 Synthetic routes to diaryliodonium salt s…………..…..…...……....93 3.1.2 Applications of diaryliodonium salts…………………………..…96 3.1.3 Electrosynthesis of diaryliodonium salts………………..………..97 3.2 Results and discussion……………………………..………………….100 3.3 Conclusions………………………………..…………………………..104 3.4 Experimental………………………………..….………………………105 3.5 References…………………………..…………………………………109 4. The synthesis of carbamates via a Hofmann rearrangement and the use of electrochemical mediators in flow 4.1 Introduction .………………...…………………………………….…..113 4.2 Electrochemically induced Hofmann rearrangement…….……..…….119 4.3 Results and discussion………………………..…………………..…....122 4.3.1 Electrochemically induced Hofmann rearrangement in flow…..122 4.3.2 Electrogenerated bases……………………………..……………129 4.3.3 Oxidation of alcohols in flow……………………….…………..132 4.4 Conclusions………………..…………………………………………..136 4.5 Experimental……………………………...……………………………137 5.6 References…………………………..…………………………………142 5. Electrochemical trifluoromethylation of olefins in flow 5.1 Introduction…………………………………..………………………..146 5.1.1 Fluorine in nature and so ciety…………………………..……….146 5.1.2 Fluorine in medicine……………………..………………………149 5.2 Methods of fluorination…………………………..……………………152 5.2.1 Direct fluorination………………………………..……………..152 5.2.2 Electrochemical fluorination………………………..…………..157 5.2.3 The “Building block” method……………………………..……159 5.2.4 Fluorinations using microreactors……………....…………….......161 5.3 Results and discussion………………………………………..……….164 5.3.1 Bistrifluoromethylation………………….……………………...166 5.3.2 Dimerisati on…………………………………..…………………170 5.3.3 Hydrotrifluoromethylation…..…………………….……………174 iii 5.3.4 Substitution…………………………………………..…………..178 5.3.5 Trifluoromethylacetamidation………………….………………..179 5.4 Conclusions…………………………………..………………………..181 5.5 Experimental…………………………...………………………………181 5.6 References……………………..……………………………………….185 6. Conclusions…………….…..……………..……………………………………....189 7. Appendices 7.1 Part A schematic……………………………..………………………...192 7.2 Part B schematic……………………………………..………………...193 iv Abstract Organic electrochemistry provides a straight forward and efficient method for the generation of a wide variety of reactive intermediates. It does however; suffer from limitations such as the need for supporting electrolytes. The scale up process can also be difficult from preparative to large scale batch syntheses. Interest in the field of microreactor technology has grown over the last 10 to 20 years. This is due to increasing efforts in making organic chemistry a “greener” process, using less solvents and expensive chemical reagents. Combining these two fields of chemistry provides a platform for making organic electrochemistry more appealing to chemists and industry, although the technology is still in its infancy. As there are no commercially available microreactors for electroorganic synthesis, one has been designed and fabricated before it can be used for electroorganic syntheses in a flow environment. v Abbreviations AcOH - Acetic acid Br- Broad Calcd - Calculated DABCO - 1,4-diazabicyclo[2.2.2]octane DAST – diethylaminosulfur trifluoride DBU - 1,8-Diazabicyclo[5.4.0]undec-7-ene DME – Dropping mercury electrode DMF - N,N-Dimethylformamide DMP – Dess-Martin periodinane DMSO - Dimethyl sulfoxide EGB – Electrogenerated base EHD - Electrohydrodimerisation EWG – Electron withdrawing group EI – Electron impact Eq. - Equivalent FEP – Fluorinated ethylene propylene FTMS – Fourier transform mass spectrometry GCMS – Gas chromatography mass spectrometry GLC – Gas-liquid chromatography h - Hour HPLC – High performance liquid chromatography HRMS – High resolution mass spectrometry vi IBX – Iodoxybenzoic acid IR – Infrared J – Coupling constant (Hz) Lit. - Literature m-CPBA – m-chloroperbenzoic acid m - Multiplet Min – minute Mol - Mole m.p – melting point NBS - N-Bromosuccinimide NFSI – N-fluorobenzenesulfonimide NMR – Nuclear magnetic resonance NSI – Nanospray ionisation PEEK – Polyether ether ketone PET – Positron emission tomography PIDA – (Diacetoxyiodo)benzene Ppm – Parts per million PTFE – Polytetrafluoroethylene RT – Room temperature s - Singlet SPS – Solvent purification system SET – Solution electron transfer SCE – Standard calomel electrode vii TBACl – Tetrabutylammonium chloride TBAF – Tetrabutylammonium fluoride TBAI – Tetrabutylammonium iodide TEAB – Tetraethylammonium bromide TEMPO - 2,2,6,6-Tetramethylpiperidinyloxy TFA – Trifluoroacetic acid TLC – Thin layer chromatography TOF – Time of flight UV – Ultraviolet viii Acknowledgements Firstly I would like to thank my supervisor at Cardiff University, Thomas Wirth, for the opportunity to study and help throughout the project. I would also like to thank my industrial supervisor Will Gattrell of Prosidion Ltd for the opportunity to spend time at the company. Many thanks to Professor David Barrow of Cardiff School of Engineering for help designing the microreactor, and a big thank you to Alun, John and Steve of the chemistry workshop for help fabricating the microreactor and continual assistance throughout the project, and also to the other support staff. I would also like to thank the Wirth group members, past and present: Guillaume, Mat, Baker, Rich, Mike, Umar, Pushpak, and the many other people I have spent time with at Cardiff University. One last thank you to all of my family who have supported me for the duration of my time at Cardiff University. ix Chapter 1 Chapter 1 General Introduction 1 Chapter 1 1. Electroorganic chemistry 1.1. History of electroorganic chemistry Historically electrochemistry was born in 1800 when Alessandro Volta invented the first electric battery 1 that could supply a current to an electric circuit making the field a possibility. It was also in this year that the first electrochemical reaction was reported, the decomposition of water to oxygen and hydrogen reported by Nicholson.2 However, the first electroorganic synthesis was reported by Faraday much later in 1834 showing that after electrolysis of an acetate salt the products were found to be carbon dioxide and ethane when conducted on platinum electrodes (Scheme 1.1). 3,4